Inhibition of GASC1

a gasc1 and inhibitor technology, applied in the field of gasc1 inhibition, can solve the problems of chromosomal aberration, cancer, and inability to reverse trimethylated lysine marks, and achieve the effects of low ionic strength, high stringency, and low stringency

Inactive Publication Date: 2013-04-16
UNIVERSITY OF COPENHAGEN
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Benefits of technology

The present invention is about a method to identify, screen, characterize, or design a compound that can control the activity of a protein called JMJD2 subfamily. This method can be used to quickly screen large numbers of compounds to find potential treatments for cancer, especially prostate cancer. The method is useful for the pharmaceutical industry. Another alternative method involves a homogenous binding assay where the label on the protein changes when it binds to its specific agent, allowing for detection or quantitation of the protein without needing a separation step.

Problems solved by technology

However, LSD1 is unable to demethylate tri-methylated lysine H3-K4, most likely due to the absence of a protonated nitrogen required for oxidation4.
Thus, although the identification of LSD1 and FBXL11 as histone demethylases constituted important milestones for epigenetic research demonstrating the dynamic regulation of methyl marks, they have not resolved the question of the reversibility of tri-methylated lysine marks.
As documented by studies of the SUV39H1 knockout mouse, loss of the tri-methyl variant of the H3-K9 mark results in chromosomal aberrations and predisposes to cancer.

Method used

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  • Inhibition of GASC1
  • Inhibition of GASC1
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[0120]In an effort to identify proteins interacting with tri-methylated variants of H3K9, HeLa nuclear proteins were affinity purified using biotinylated H3 peptides immobilized on streptavidin-agarose. Synthetic 43-mers mimicking the whole N-terminal tail of histone H31-40, either un-methylated or tri-methylated at lysine 9, were used in the in vitro binding experiments. Bound proteins were eluted from the agarose-matrix, separated by SDS PAGE, silver stained and identified by mass spectrometry. Several proteins were specifically enriched on tri-methylated H3K9 as compared to un-methylated H3K9, supplementary figure S1.

[0121]Among the proteins identified was the Jumonji protein GASC1 (FIG. 1a). Due to the presence of a Jumonji domain JmjN and a related JmjC domain the protein is also denoted JMJD2c8, 9 (FIG. 1a). The Jumonji protein family comprises a diverse group of proteins that belong to the α-ketoglutarate-dependent oxygenase superfamily. These proteins regulate various cellul...

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Abstract

The present invention provides a method of testing the ability of a test compound to bind to and optionally modulate the activity of a protein of the JMJD2 subfamily of Jumonji proteins. The method comprises incubating a test compound with a protein of the JMJD2 subfamily of Jumonji proteins, a co-factor of said protein and, optionally, a substrate for demethylation. The method of the invention can be used for screening large numbers of compounds to identify a group of compounds that are candidate compounds for clinical use for treatment of certain cancers especially prostate cancers. Other compounds that do not have activity in the screening assays can be eliminated from further consideration as candidate compounds. The method of the invention therefore has utility in the pharmaceutical industry.

Description

FIELD OF INVENTION[0001]The present invention relates to a method for identifying compounds that are capable of acting as activity modulators of the JmjC domain containing proteins and which are useful for prevention and / or treatment of diseases in which genomic instability is involved in the pathogenesis.BACKGROUND OF THE INVENTION[0002]Methylation of lysine and arginine residues on histone tails constitutes important epigenetic marks delineating transcriptionally active and inactive chromatin. For instance, methylation of lysine 9 on histone H3 (H3-K9) is associated with epigenetically silenced chromatin1-3. In contrast to other histone modifications such as acetylation and phosphorylation, methylation has been regarded as irreversible because of the high thermodynamic stability of the N—CH3 bond. Recently however, Shi and coworkers4 identified the protein LSD1, a nuclear amine oxidase homologue, as a histone demethylase highly specific for mono- and di-methylated H3-K4. This enzy...

Claims

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Application Information

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Patent Type & AuthorityPatents(United States)
IPC IPC(8): G01N33/53G01N31/00
CPCC12Q1/48G01N33/6875Y10T436/10G01N2500/00G01N2333/91011
InventorCLOOS, PAULAGGER, KARLCHRISTENSEN, JESPERHANSEN, KLAUS H.HELIN, KRISTIAN
OwnerUNIVERSITY OF COPENHAGEN